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DEMENTIA BRINGING EVIDENCE & EXPERIENCE TO DRUG THERAPY DECISION POINTS October 2014 INSIDE Impaired Cognition, Function & Behaviours: Drug Related Considerations Pg 3: Cholinesterase Inhibitors (ChEI) in Dementia Initial Assessment Ö Assess for reversible causes Pg 7: Geri‐RxFiles ‐ Dementia & Cognitive Impairment Š drug causes e.g. anticholinergic load Š B12 deficiency Ö Plan for future uncertainties Š advanced care directives Š power of attorney in place Pg 12: Geri‐RxFiles – Anticholinergics Reference List Pg 13: Geri‐RxFiles – Dementia: Behavioural & Psychological Symptoms (BPSD) Upon Early Diagnosis of Dementia Ö Note the role & value of non‐drug measures (see pg 6) on quality of life Ö Decide whether a trial of cholinesterase inhibitors (ChEIs) is indicated Ö Determine whether a trial of a ChEI is desirable to the patient/family RESOURCES & LINKS (FOR FAMILY): ÖAlzheimer’s Society: http://www.alzheimer.ca/en ÖFirstLink‐SK: http://www.alzheimer.ca/en/sk/We‐
can‐help/First‐link‐start REAL‐LIFE CHALLENGES Clinician quotes ÖI recommend trying a ChEI, but they really don’t work. ÖIt’s not easy to explain benefits & harms to patients & families. ÖCurrent guidelines recommend a ChEI trial, but clinicians seem divided on this. ÖIt’s hard not to overestimate or underestimate concerns re: medications in dementia. A balanced approach eludes us! NEW AT RXFILES RxFiles Drug Comparison Charts – 10th Edition Book – Oct 2014. & Geri‐RxFiles – May 2014. Cholinesterase Inhibitors (ChEI) for Alzheimer’s Dementia Benefits/Advantages ‐ Stabilizing or slowing progression of Alzheimer’s dementia in terms of cognitive testing (modest) Harms/Disadvantages ‐ Poor tolerability ŠAny adverse effect, NNH=12 ‐ gastrointestinal upset ‐ marked improvement, uncommon, NNT=42 ‐ increased risk of falling ‐ at least minimal improvement, NNT=12 ‐ urinary incontinence ‐ cognitive stabilization, NNT=7 Š Stimulating, sometimes resulting in (Note: benefit was not noticeable to agitation or worsening of behaviour the patients taking the ChEI in trials) ‐ Cost considerations ‐ Stimulating, sometimes resulting in less ‐ Undesirability of taking one more drug apathy ‐ Foster unrealistic hopes that may delay dealing with future planning Limitations: Evidence fails to show functional improvement or preservation of independence. Studies have not involved typical patients; harms likely more frequent. What to expect from not trying ChEI but initiating non‐drug measures? Benefits/Advantages Harms/Disadvantages ‐ May miss out on the chance that there ‐ Expect improvement in quality of life may be some improvement that is ‐ Avoid the side effects of the ChEI clinically relevant for a period of time. ‐ Results in one less drug & drug cost ‐ Note: rate of cognitive stabilization for placebo in trials was 51% (vs 66% for ChEI) Ö Provide a realistic picture of potential benefits, harms & costs of trialing versus not trialing a ChEI in the context of patient values. Discuss with patient and/or family. Ö Consider a trial of a ChEI (e.g. donepezil) when suitable and desired. Ö Monitor & reassess! The decision to continue depends on realizing adequate benefit and tolerability. Ö Note: ChEIs less likely to be effective in non‐Alzheimer’s dementias. Memantine is an alternative option with its own advantages & disadvantages. DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region (SHR). Neither the authors nor Saskatoon Health Region nor any other party who has been involved in the preparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Any use of the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR, its employees, servants or agents. Readers are encouraged to confirm the information contained herein with other sources. Additional information and references online at www.RxFiles.ca Copyright 2014 – RxFiles, Saskatoon Health Region (SHR) Behavioural & Psychological Symptoms of Dementia (BPSD) Management Ö Non‐drug strategies will often be the most useful! Ö Pharmacological management has a role in addressing certain symptoms, especially when patient or caregiver safety is threatened. Ö When medications are used (e.g. risperidone, quetiapine for aggression, especially when severe and there is risk of harm to patient or caregiver): Š trial, with caution, the most appropriate medication for the symptom Š monitor for evidence of relative benefit vs harm Š reassess for possible taper & discontinuation every 3 months Ö See Pg 13 for a detailed discussion of BPSD Behind the Scenes at RxFiles RxFiles hosts the… National Academic Detailing Conference: Focus on Dementia & Polypharmacy. Continuing Professional Development, Schulich School of Medicine & Dentistry, Western University, in collaboration with RxFiles Academic Detailing Program and the Canadian Academic Detailing Collaboration (CADC) hosted a 2.5 day National Academic Detailing Conference in September, 2014. The conference was jointly branded by the three organizations. Our Guest Facilitator, Frank May Frank May comes from Australia, and fortunately for us, he is often passing through North America and able to slip in a visit to help out with conferences and workshops like ours. His important contribution to the academic detailing community in Canada was recognized by the CADC during the conference. Hearing from family & staff… The conference started off at a long‐term care (LTC) home in Saskatoon where we listened to family members, LTC staff, and a LTC family physician tell their stories and experiences in a panel discussion format. Lots of input & discussion… Joel Lamoure entertains & informs… Joel shared the results of an award winning project by the Schulich School of Medicine & Dentistry, Western University, London, ON. The conference was made possible through a grant from Schlulich, for which we were all very grateful. The conference involved 11 family physicians, 2 geriatric psychiatrists, & a host of others from RxFiles and the CADC community from BC, MB, ON and NS. Thanks to everyone!!! And of course everyone had a tiny bit of time to just be themselves. ACKNOWLEDGMENTS: We would like to thank those who contributed to our conference &/or the development & review of this newsletter including
Dr. L. Thorpe, Dr. M. Davidson, Dr. M. McLeod, Dr. B. Martens, Dr. J. Alport, Dr. V. van der Merwe, Dr. N. Olsen, Dr. K. Roelens, Dr. S. Bugden, Dr. B. Schuster, D. Bunka, A. Crawley, the families & staff at Sunnyside, & the rest of the RxFiles team. L. Regier, J. Bareham
Pg 2
RxFiles
www.RxFiles.ca - Oct 2014
A Crawley BSP, SHR Pharmacy Resident; L Regier BSP; L Kosar BSP, MSc; B Jensen BSP; J Bareham BSP MSc
Cholinesterase Inhibitors (ChEI) in Dementia ‐‐‐‐‐ HIGHLIGHTS ‐‐‐‐‐ 9 Cholinesterase inhibitors (ChEI) may offer a modest benefit in stabilizing or slowing progression of Alzheimer’s dementia. This benefit often competes with significantly poor tolerability (e.g. gastrointestinal: diarrhea, nausea; bradycardia, risk of falling, urinary incontinence, sometimes behavioural disturbance) & questionable clinical usefulness. 9 A patient‐centred approach is essential when considering trial of a ChEI. Offering a balanced description of benefits, harms & realistic expectations will help patients and families to make decisions on trialing, continuing vs tapering, or discontinuing therapy. Employing non‐drug measures without a ChEI will often be preferred. 9 Avoid or limit the use of anticholinergics in combination with a ChEI, as use may diminish or negate benefits of the ChEI. When urinary incontinence and dementia co‐exist, a decision must often be made regarding which one to treat. What are the indications for cholinesterase inhibitors? ARICEPT
REMINYL
EXELON
Cholinesterase inhibitors (donepezil , galantamine , and rivastigmine ) are medications designed to prevent the breakdown of the neurotransmitter acetylcholine. Insufficient levels of acetylcholine are thought to be a factor in the cause and progression of Alzheimer’s disease. While originally designed and marketed for mild to moderate Alzheimer’s disease (MMSE 10‐26), ChEIs have now been studied in multiple types of dementia. It is important to remember that prescribing for dementia beyond Alzheimer’s disease is usually off‐label. Such use may not meet the indication criteria required for drug plan coverage. Of further importance is that differentiating between the various types of dementia is challenging; many patients present with a mixed pathogenesis. Anecdotally, ChEIs may be stimulating in some patients resulting in either a benefit (less apathy), or harm (more agitation and behaviour disturbance). Table 1: Cholinesterase Inhibitors: Potential Role Based On Evidence for Benefits vs Harms Description Evidence for ChEI (Benefits/Indications) Cognitive Outcome Meta‐analysis ‐ trials of 12‐54 weeks1 NNT=7 stability or improvement (95%CI 6‐9) NNT=12 minimal improvement (95%CI 9‐16) NNT=42 marked improvement (95%CI 26‐114) NNH = 12 any adverse effect (95%CI 10‐18) Note: given that patients in trials were less severe with fewer co‐morbidities, some expect less benefit, but more harm
in real life.
Parkinson’s Parkinson’s disease frequently leads RCTs n = 14‐550 with rivastigmine & donepezil Rivastigmine & donepezil can be expected to Disease to dementia. May present as have shown small benefits of clinically increase MMSE by ~1 point over 10‐24 (PD) Alzheimer’s type or Lewy Body type. questionable significance.2 Rivastigmine weeks versus placebo.2 approved for mild‐moderate PD dementia. Can exacerbate parkinsonism.6 Dementia occurs due to a loss of RCTs n = 592‐974 with donepezil, galantamine, Non‐significant for stability or improvement Vascular blood flow to the brain. Executive & rivastigmine have shown small benefits vs placebo; positive change of ~2 points over Dementia dysfunction with sparing of memory of clinically questionable significance.3,4 24‐26 weeks in the ADAS‐Cog test vs (VaD) is typical. placebo.4 Shares many symptoms in common Rivastigmine RCT n = 120 showed no benefit Cholinesterase inhibitors unlikely to be Lewy Body with Parkinson’s disease. in cognition over 20 weeks vs placebo .42 effective for improving cognition; may be Dementia Characterized by visual considered for hallucinations.2,5, Expert opinion (LBD) hallucinations; falls are common. Frontotemporal Strong genetic pattern of inheritance; FTD does not appear to be associated with Cholinesterase inhibitors unlikely to be begins earlier in life than AD and acetylcholine.7 ChEI therapy has not been effective. Dementia rapidly progresses. Changes occur evaluated in a placebo‐controlled trial. (FTD) first to speech and personality. Some evidence suggests ChEIs may actually worsen behaviour.46 Alzheimer’s Disease (AD) Associated with brain changes referred to as plaques and tangles. Initial forgetfulness progresses to profound memory loss. Patients eventually require full‐time care. Many RCTs n = 161‐978 show a modest benefit. All three ChEIs approved for treatment of mild‐moderate AD dementia; donepezil approved for severe AD dementia.† approved=official indication, Health Canada GREEN=modest benefit YELLOW=questionable benefit RED=unlikely benefit †Rivastigmine approved for severe in USA Is ChEI effectiveness clinically significant? Given the modest potential for benefit, a decision to treat means carefully weighing the potential harms. •
•
•
Consider offering most patients with a diagnosis of mild to moderate Alzheimer’s disease a cholinesterase (See section: 13;CCCDT04
When should inhibitor trial.
Patient and family opinion, once adequately informed, is highly important. cholinesterase Consider the stage of dementia the medications are being started in. While these drugs have been studied in inhibitors be severe dementia, keeping a MMSE stable at 7 may not be valuable. Achieving stabilization or improvement of avoided or MMSE from 16 to 17 on the other hand may be significant to some patients or families. discontinued?)
Consider the premise of non‐responders and responders. There is evidence that some patients (~10%) will 8
experience a significant effect after starting a ChEI (perhaps a 4 point increase in MMSE). Unfortunately, patient response cannot be predicted ‐ other patients (~10%) will experience a rapid decline in cognitive function. {Placebo has benefit in trials!} “Once you have seen one dementia patient, you have seen one dementia patient.” 2 Pg 3
RxFiles
www.RxFiles.ca - Oct 2014
A Crawley BSP, SHR Pharmacy Resident; L Regier BSP; L Kosar BSP, MSc; B Jensen BSP; J Bareham BSP MSc
What are the cost considerations? •
Generic availability has made all ChEIs more affordable, with a monthly cost around $70 per month. (The cost of these 9
drugs was previously around ~$200/month.) Despite high hopes, ChEIs have not been shown to reduce health system costs through decreasing hospitalizations or nursing 10‐12 home admissions. (AD2000)
•
To initially qualify for Saskatchewan EDS coverage, patients must: 1. Have a diagnosis of (probable) Alzheimer’s disease 2. Have a MMSE score of 10‐26* 3. Have completed a Functional Activities Questionnaire (FAQ)** 4. Discontinue all anticholinergic drugs*** 0‐9 severe *A copy of the MMSE & instructions may be found at: http://www.albertahealthservices.ca/hp/if‐hp‐ltc‐pharm‐cholinesterase‐inhibitor‐self‐study‐module.pdf **A copy of the FAQ may be found at: http://consultgerirn.org/uploads/File/trythis/try_this_d13.pdf ***Refer to RxFiles Anticholinergics: Reference List of Drugs with Anticholinergic Effects MMSE Dementia Scoring
10‐19 20‐26 moderate mild 27‐30 pre‐clinical note that language barriers & level of education must be considered when scoring as they may decrease the score. http://www.rxfiles.ca/rxfiles/uploads/documents/members/Psyc‐anticholinergic‐Ref%20List%20SPDP‐complete.pdf Assessment of MMSE and FAQ must be completed by prescribing physician or nurse practitioner; documentation to be signed and submitted may be found here: http://www.health.gov.sk.ca/form‐he599 To continue to qualify for Saskatchewan EDS coverage, patients must: 1. After first assessment (3 months), demonstrate improvement of +2 on MMSE or ‐1 on FAQ. 2. After all future assessments (every six months), not have both a >2 point reduction in MMSE and a ≥1 point increase in FAQ. 3. Remain above MMSE of 10 at all times. Patients with MMSE improvement to >26 continue to 4. Continue to not use drugs listed with substantial anticholinergic effect. qualify for coverage. Reassessment of MMSE and FAQ may be completed by any licensed health care professional; final documentation must be signed and submitted by prescribing physician or nurse practitioner (http://www.health.gov.sk.ca/form‐he599) Table 2: Typical Dose and Cost of Cognitive Therapy Medications antagonist NMDA Cholinesterase Inhibitors SK/NIHB coverage? Donepezil EDS / Prior approval ARICEPT, g Galantamine REMINYL, g EDS / Prior approval Rivastigmine EXELON, g EDS / Prior approval Memantine EBIXA, g NO: 2/⊗ Dose Cost/month Initial: 5mg po daily Usual (max): 5‐10mg po daily $66 $66 Initial: 8mg ER po daily Usual (max): 8‐24mg ER po daily Initial: 1.5mg po BID
Usual (max): 1.5‐6mg po BID Patch: 4.6mg or 9.5mg applied once daily $68 $68 $70 $70 $170 Initial: 5mg po daily Usual (max): 5‐10mg po BID $39 $67‐125 (10mg) (10mg) (24mg) (6mg) Table 3: Cholinesterase Inhibitor Drug Interactions Pharmacodynamic Antipsychotics Anticholinergics Beta‐blockers Pharmacokinetic CYP3A4 inhibitors (e.g. erythromycin, clarithromycin, fluconazole, ketoconazole) CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, quinidine) CYP inducers (e.g. rifampin, carbamazepine) Nicotine / Smoking Drug donepezil galantamine rivastigmine Result 9 9 9
9 9 9 9 9 9 potential Parkinsonian symptoms
diminished therapeutic effect bradycardia 9 9 ↓ ChEI metabolism and Ç levels 9 9 9 9 9 Ç ChEI metabolism and ↓ levels Pg 4
RxFiles
www.RxFiles.ca - Oct 2014
A Crawley BSP, SHR Pharmacy Resident; L Regier BSP; L Kosar BSP, MSc; B Jensen BSP; J Bareham BSP MSc
What about patients taking anticholinergics for incontinence? Anticholinergic incontinence medications can impair cognition/cognitive performance. 36
• In patients with dementia, anticholinergic medications should be avoided. • In non‐demented patients who are experiencing delirium from an anticholinergic (e.g. DITROPAN, DETROL, TOVIAZ), best practice is to discontinue the anticholinergic and use nonpharmacological therapy (moderate fluid intake, scheduled voiding, absorbent products, etc.). [A helpful guide: www.cnca.ca/pdf/Promoting_Continence_Using_Prompted_Voiding.pdf ] Cholinesterase inhibitors can cause or worsen urinary incontinence. 37
• Even if not taking a ChEI, the prevalence of urinary incontinence in Alzheimer’s disease patients is >50%. • In patients who are experiencing intolerable incontinence with a ChEI, the first consideration should be to decrease the dose of ChEI and/or to use nonpharmacological therapy. Stopping the ChEI may be necessary. Given the modest benefits of ChEIs, it is necessary to prioritize between anticholinergic & cholinergic therapy. • This is a situation that may be described as “picking your organ”. Using anticholinergics for the bladder diminishes the 15, 38 therapeutic effect of the ChEI on cognition, and vice versa.
38
• Theoretically, choosing a newer anticholinergic for urinary incontinence could lead to fewer CNS side effects. M3 receptors are less concentrated in the brain, which has lead to the development of M3‐selective agents (e.g. solifenacin VESICARE
ENABLEX
, darifenacin ). Hydrophilic compounds have a limited ability to cross the blood brain barrier, which has lead to TROSEC
the development of agents such as trospium . In one study, darifenacin did not affect cognitive function in healthy 39
16
seniors after two weeks. In another, trospium was undetectable in the CNS of healthy adults. These drugs have not been studied in patients with dementia. Watch out for other causes of incontinence in the elderly37
Refer to RxFiles Urinary Incontinence Chart. Šheart failure → fluid overload • Note that Saskatchewan Health will discontinue drug Šbenign prostatic hyperplasia → obstruction coverage for ChEIs when they are combined with Šconstipation → fecal impaction highly anticholinergic drugs, as per list on Pg 12. Šimmobility → increased time to reach bathroom • Memantine has a unique mechanism of action (see Šurinary tract infections → urinary urgency below). It may be considered in patients who do not Šmedications e.g. diuretics, antipsychotics, antidepressants, sedatives tolerate cholinesterase inhibitors. When should cholinesterase inhibitors be avoided or discontinued? Continual assessment of patients on cholinesterase inhibitors is paramount! . •
•
31%
¾
•
•
•
•
•
21%
15%
14%
14% 17
Common side effects of ChEIs are nausea , vomiting , dizziness , diarrhea , and headache . Behaviour disturbances may also occur. It is essential to regularly ascertain whether side effects outweigh the benefits of therapy. 17
(Tolerance to side effects can occur over time, especially if the dose of cholinesterase inhibitor is slowly titrated. ) Avoid cholinesterase inhibitors in: patients with cardiac conduction abnormalities (e.g. sick‐sinus syndrome, bradycardia). Syncope, decreased heart rate, and falls have been associated with cholinesterase inhibitors. patients with active peptic ulcer disease. Cholinesterase inhibitors may increase gastric acid secretion and ulcer risk. ¾
Be cautious in patients likely to experience a drug interaction (see Table 3). Start low and go slow when initiating therapy. Evidence suggests that in patients whose cognitive scores decline rapidly (i.e. deterioration in ADAS‐cog of 4 points or 19
MMSE of 2 points over six months), ChEIs are no better than placebo. There is considerable debate regarding the best approach for patients who decline from mild or moderate dementia into severe dementia. Cholinesterase inhibitors have been shown to continue to be statistically effective over placebo in 21
preventing cognitive decline in patients with severe dementia. However, this may not translate into an improvement in quality of life. Take into account the patient and patient's ChEI Drug Holidays? family’s perspectives. There is controversy regarding stopping cholinesterase If discontinuing a ChEI, a tapering process reduces the risk of inhibitor therapy, and then restarting if cognitive decline 47
rebound constipation and other side effects. Try decreasing accelerates. There is limited evidence that patients in this the dose by 25‐50% every 1‐2 weeks. situation may not regain function when the drug is Be aware that many patients will stop ChEIs without talking to 20
restarted; neuroprotective effects may have been lost. their physician. It is common for at least one‐third of patients On the other hand, discontinuation in patients with to discontinue therapy within the first six months due to side 46
severe dementia may be well tolerated.
17,18
effects, forgetfulness, cost, or a perceived lack of benefit. 2=non‐formulary Sask ⊗=not covered by NIHB =Exceptional Drug Status Saskatchewan =prior approval NIHB AD=Alzheimer’s disease ADAS‐Cog=cognitive section of the Alzheimer’s Disease Assessment Scale (Scale 0‐70; lower score better) ChEI=cholinesterase inhibitor CNS=central nervous system CYP=cytochrome P450 EDS=Exceptional Drug Status (SK) FAQ=Functional Activities Questionnaire (Scale 0‐30; lower score indicates greater function) FTD=frontotemporal dementia LBD=Lewy body dementia MMSE=Mini Mental State Examination (Scale 0‐30; higher score better) NNH=number needed to harm NNT=number needed to treat NS=non‐significant PD=Parkinson’s disease RCT=randomized controlled trial VaD=vascular dementia Pg 5
RxFiles
www.RxFiles.ca - Oct 2014
A Crawley BSP, SHR Pharmacy Resident; L Regier BSP; L Kosar BSP, MSc; B Jensen BSP; J Bareham BSP MSc
What about memantine? •
EBIXA
Memantine is a NMDA antagonist and therefore presents an alternate mechanism of action for treatment of 22
dementia. Memantine has been studied against placebo, against ChEIs, and in combination with ChEIs. It has an approved indication for moderate to severe dementia Table 4. When to consider memantine instead of a ChEI
caused by Alzheimer’s disease. Memantine does not 23
Advantages Disadvantages appear to be effective in mild AD. 1. Unique side effect profile. 1. Cost. Not covered by the SK Memantine may have a lesser magnitude of effect 24
May be useful if patient Drug Plan under any than ChEIs. It has been associated with a decrease experiences urinary circumstance. $125/month in aggression & agitation, although this evidence is 25,40
incontinence, diarrhea, or 2. Not approved, nor effective not rigorous. Theoretically, using memantine in nausea with ChEI. for mild dementia. combination with a ChEI is reasonable, but it does not 3. Twice daily dosing. 2. Approved for moderate and appear to convey additional benefit; it may also be 4. ?Cardiovascular risk: in severe dementia. associated with more side effects.26 DOMINO Memantine retrospective cohort study, 3. May be helpful for patients is not covered by the Saskatchewan Drug Plan (cost: found to have increased risk of who are aggressive, $125/month). Memantine may be considered when 25,40 post‐hoc data only
HR 1.33
HR 1.31
MI
agitated.
and cardiac death
ChEIs are not tolerated or are contraindicated. 41
4. Minimal drug interactions. compared to donepezil;
Side effects include: dizziness, drowsiness, confusion, manufacturer reports increased insomnia, and headache. Caution is required if using rates of cardiovascular side memantine in patients with a history of heart disease HF, HTN
42
effects
versus placebo. due to an association with adverse CV events. •
•
What about vitamin E, vitamin B12, omega‐3s, ginkgo, atorvastatin…, for the prevention of dementia? There is insufficient evidence to recommend these products.
27‐31,43
(see also Geri‐RxFiles – Dementia and Cognitive Impairment) Non‐Pharmacological Measures for Dementia Treatment34,35 “It is not how much we do – it is how much love we put into the doing.”
‐Mother Teresa 33
Non‐pharmacological interventions may be more efficacious than pharmacological interventions! 9 Behavioural therapy: consider Antecedents, Behaviours, & Consequences (ABC). Gather information about manifestations of behaviour and the sequence of events leading to it; changing antecedents or consequences can lead to a change in behaviour. 9 Schedule “pleasant events” e.g. audio‐books, crosswords, tea with others, personal grooming, exercise. 9 Art therapy, music therapy, aromatherapy, & activity therapy may offer significant benefit. 9 Reminiscence therapy: reliving of past pleasurable experiences. 9 Adjust environment to ability (e.g. safe objects for manipulation; reduced clutter; familiar cues like paint around the toilet, high‐contrast steps; increased natural lighting; posted signs). 9 Simulate presence therapy – audio‐recording of family member talking about past positive events; played strategically. Refer to RxFiles An Introduction to the Various Types of Dementia, Their Management & Treatment Beware of thinking “nothing can be done”. Non‐drug therapy often has a substantial impact!!! ‐‐‐‐‐ PEARLS ‐‐‐‐‐ • Ensure that patients with dementia are not taking drugs with anticholinergic properties. Refer to Anticholinergic List, Pg 12. • Prescribe ChEIs with pre‐defined criteria for how to evaluate efficacy. Constant re‐assessment is a must if one is to avoid excessive costs and excessive side effects for patients and their families. For some patients, it may be reasonable to trial a ChEI. After trialing, it will often also be reasonable to taper & stop. 17
• Donepezil may be the best tolerated ChEI. Dosing donepezil at bedtime & with food may improve GI‐related tolerability. 32
If insomnia occurs, dosing may be changed to the morning. • Intolerable side effects are often best treated by decreasing the dose, switching to a different agent, or tapering & discontinuing therapy. Copyright 2014 – RxFiles, Saskatoon Health Region (SHR) www.RxFiles.ca ‐ References available on line at www.rxfiles.ca Pg 6
Dementia & Cognitive Impairment The Various Types of Dementia1 Dementia is a term that describes a decline in a variety of functions (e.g. memory, language, motor activities, ability to recognize or identify objects, complex decision‐
making) which eventually causes a person to have difficulty performing everyday activities. There are different types of dementia which vary in their onset of symptoms, type of symptoms, eventual outcome & response to interventions. Although Alzheimer's dementia is the best known, other dementias are common, & individuals may have a mix of various dementias. Alzheimer’s Disease (AD) • AD is associated with typical changes in the brain, often referred to as "plaques", "tangles" & cerebral atrophy (brain shrinkage), which are likely caused by a combination of genetic & environmental factors. While the brain undergoes structural changes, the diagnosis of AD is determined based on a general medical & psychiatric exam (cognitive testing is integral). The diagnosis of AD can only be confirmed upon autopsy. • There is usually a slow, progressive decline, although individuals occasionally appear to have faster declines at certain points, especially at times of major change, such as widowhood or a move to a new home. • Short‐term memory problems are usually the first sign, but over time the individual develops problems in all other areas of functioning so that he/she will need full‐time care.
• Life expectancy: o On average 8 to 10 years after symptoms begin o If diagnosed in 60s & early 70s, 7 to 10 years o If diagnosed in 90s, 3 years Frontotemporal Dementia (FTD) • FTD has a stronger genetic pattern of inheritance than AD & vascular dementia (VaD), and usually starts earlier in life (often by the 40s or 50s). There are a few different types of FTD. Some affect mostly speech & language in the early stages, but the FTD behavioural variant (FTD‐bv) typically affects behaviour first & can be difficult to differentiate from other psychiatric problems. • Damage is initially limited to the frontal & temporal lobes, which results in a very different pattern of symptoms than AD. Affected individuals usually have an early alteration in their speech, language, personality or social behaviour, before any memory changes occur. The individual often displays poor judgment & inappropriate, disinhibited behaviour more similar to very young children (such as putting everything in the mouth). Certain movements may be performed repetitively without any apparent reason. • Speech may be very unusual, with repetition of words & sounds, & choppy rhythm. Eventually the individual becomes mute & often also develops difficulties with swallowing. This is particularly common if the individual develops ALS (also known as Lou Gehrig's Disease) with the FTD, which occurs in a sizable percentage of affected individuals. • Over time, problems arise in other functions as well, resulting in a global dementia, requiring a highly structured environment. • Life expectancy: 6 to 8 years after symptoms begin www.rxfiles.ca Lewy Body Dementia (LBD) • LBD is associated with similar microscopic changes as Parkinson's Disease (PD), but clinically presents with earlier short‐term memory loss, and later Parkinsonism (such as tremor, balance & walking problems & stiffness). Impairment in attention, executive functioning (complex thinking & judgment) & visuo‐spatial skills occurs earlier than in AD. There is also more daily fluctuation in all of these abilities than in AD. • Well‐formed & detailed visual hallucinations are common, especially in the evening, but unfortunately, the usual treatment of these symptoms is with antipsychotics, which cause worsening of Parkinson's type symptoms; however, hallucinations do not always warrant treatment unless they are causing distress to the individual or caregivers. • Falls are very common. • Unlike AD, in the early stages of LBD the abilities of the affected individual often fluctuate drastically from day to day, or even during the course of a single day. This can often be puzzling for those around them. • Life expectancy: 6 to 12 years after symptoms begin Parkinson’s Disease (PD) Dementia • Individuals with PD are prone to developing dementia, which might be typical AD, or more similar to LBD as described above. • Similar to LBD, there is more impairment in attention, executive function & visuo‐spatial skills than in AD. • Common difficulties include memory loss, apathy, changes in personality & mood, visual hallucinations, & paranoid delusions, especially late in the course of the disease when high doses of medications are required for the treatment of PD. Vascular Dementia (VaD) • VaD is caused by problems with small or large blood vessels, which may cause poor blood flow to parts of the brain, or bleeding into the brain. Risk factors for developing this include high blood pressure, high cholesterol, smoking, diabetes & heart disease. • Sometimes individuals with VaD have a history of obvious, clinical strokes, but more often functional changes are associated with more subtle damage seen on brain scans. • Deficits are often patchy, depending on the areas of the brain affected. The onset may be abrupt, with a stepwise decline, but may also be gradual. Sometimes individuals with VaD are stable for a long time, unlike those with Alzheimer's disease, whose decline is more progressive. • Problems with complex thinking, attention, moodiness, depression, apathy, disinhibition, agitation, aggression & occasionally psychosis (hallucinations & delusions) are more common early in the disease than is the case in AD. • Individuals with VaD tend to maintain their personality & more normal levels of emotional responsiveness until the later stages of the disease. This sometimes means that individuals with VaD are more aware of their condition and more prone to depression than individuals with AD. • Life expectancy: 5 years after symptoms begin (in many cases, death will be caused by a stroke or heart attack) Pg 7
Dementia & Cognitive Impairment www.rxfiles.ca Approach to the Treatment of Dementia ‰ Encourage regular exercise & a healthy diet. ‰ Optimize the management of co‐morbid conditions. ‰ Encourage cognitive activity (e.g. day programs). ‰ Attempt to decrease medications that may worsen cognition/function. ‰ Address/acknowledge caregiver stress (Alzheimer Society, support groups, alternative Medications That Can Cause &/or Contribute to Cognitive Impairment living situations). A P Anticholinergic Medications Psychoactive Medications See Section 24 for a more complete (usually dose‐related) list Antibiotics (e.g. fluoroquinolones [ciprofloxacin], clarithromycin BIAXIN) Anticonvulsants N Non‐Psychoactive Medications ‐ could be due to drug interactions ‐ altered pharmacokinetics can result in CNS toxicity within “normal” therapeutic range Antidepressants (e.g. paroxetine PAXIL & TCAs) ‐ all serotonergic agents, including TCAs & SSRIs, due to SSRI‐induced hyponatremia?
Antiemetics / Antivertigo (e.g. dimenhydrinate GRAVOL) ATARAX
Antihistamines / Antipruritics (e.g. hydroxyzine ) Antimuscarinics (e.g. oxybutynin DITROPAN) Antiparkinson Meds (e.g. levodopa/carbidopa SINEMET, pramipexole MIRAPEX, ropinirole REQUIP, amantadine SYMMYTREL) Antipsychotics (e.g. olanzapine ZYPREXA, quetiapine SEROQUEL, risperidone RISPERDAL) Class 1A Antiarrhythmics (e.g. disopyramide NORPACE, RYTHMODAN, quinidine, procainamide [anticholinergic], amiodarone CORDARONE) Corticosteroids (e.g. prednisone) Digoxin ‐ digoxin toxicity can occur with “normal” serum digoxin concentrations H2RAs (e.g. cimetidine TAGAMET, ranitidine ZANTAC) ‐ ↓ renal function can ↑ adverse events Hypnotics / Sedatives (e.g. benzodiazepines especially long‐acting, high dose) NSAIDs (e.g. diclofenac VOLTAREN, indomethacin) Opioid Analgesics (e.g. codeine, oxycodone, morphine, hydromorphone, fentanyl) N P A, P A A A P A, P N N N A, N P N P ‰ Refer to the Alzheimer Society – Caregiver Support & Resources The Alzheimer Society provides services & support at the time of diagnosis & throughout the duration of the disease. Individuals & their families are linked to learning, services & support as early as possible in the disease process (e.g. First Link). First Link helps to assist physicians, health care providers, & community service providers to connect individuals living with Alzheimer’s disease & other dementias, & their families, with the Alzheimer Society. Visit www.alzheimer.ca or call 1‐800‐263‐3367 (SK) for a referral form & more information
Assessment of Cognitive Function 2, 3 The assessment of cognitive function in individuals with dementia is most commonly performed using the Mini Mental State Examination (MMSE). The MMSE consists of 11 questions that test 5 areas of cognitive function: orientation, registration, attention & calculation, recall, & language. The maximum score is 30. It only takes 5 to 10 minutes to administer the MMSE and therefore it is practical to use repeatedly & routinely. The MMSE has been validated to screen for cognitive impairment with older, community dwelling, hospitalized and institutionalized adults. Severity of Impairment Mild Cognitive Impairment (preclinical) Presentation of Symptoms • Report by individual or caregiver of memory loss • Objective signs of memory impairment • No functional impairment •
•
Early, Mild •
Impairment •
(year 1 to 3 from onset •
•
of symptoms) •
•
•
•
•
Middle, Moderate •
•
Impairment •
(year 2 to 8) •
•
•
•
Late, Severe •
•
Impairment •
(year 6 to 12) •
Disoriented to date Naming difficulties (anomia) Recent recall problems Mild difficulty copying figures Decreased insight Social withdrawal Irritability, mood change Problems managing finances Disoriented to date place Comprehension difficulties (aphasia) Impaired new learning Getting lost in familiar areas Impaired calculating skills Delusions, agitation, aggression Not cooking, shopping, banking Restless, anxious, depressed Problems with dressing, grooming Nearly unintelligible verbal output Remote memory gone No longer grooming or dressing Incontinent Motor or verbal agitation MMSE Score 26‐30 21‐25 11‐20 0‐10 Note: Cognitive performance is influenced by number of years of formal education. Pg 8
Dementia & Cognitive Impairment www.rxfiles.ca 10
Treatment Considerations for Dementia Cholinesterase Inhibitors continued Currently, there are 2 classes of medications available to help stabilize cognitive function ARICEPT
REMINYL
in dementia: cholinesterase inhibitors (donepezil , galantamine , rivastigmine EXELON
EBIXA
) & a NMDA‐antagonist (memantine ). • Rivastigmine Oral o Initial dose: 1.5mg BID (in the morning & at night), with food. If well tolerated, ↑ dose to 3mg BID after at least 2 to 4 weeks. If well tolerated, ↑ dose to 4.5mg BID & then to 6mg BID, after at least 2 weeks each time. If treatment is interrupted for several days, reinitiate starting dose (i.e. 1.5mg BID) & titrate as above to reduce the risk of severe vomiting & GI bleed (e.g. esophageal rupture). 11 12
Patch o Daily applications (placed in rotation around the back, chest or upper arm) – may be more reliable method of administration in demented patients. Dose can be ↑ every 4 weeks. If treatment is interrupted for >3 days, it should be restarted with the lowest‐dose patch. Note, cost of patch is higher ($170 vs $70) than oral. When deciding whether a medication for dementia is appropriate for a particular individual, consider: potential benefits, potential adverse events, cost, quality of life, & treatment goals. Goal of Treatment To improve the quality of life for the individual & caregivers, maintain optimal function & provide maximum comfort. 456
Potential Benefits of Treatment There is currently no cure for dementia/AD & no known treatment will stop its progression. Cholinesterase inhibitors in individuals with dementia produce, on average, small improvements in measures of cognition & activities of daily living (ADL). The impact for most individuals will be modest & temporary, with not everyone responding to Meta‐analysis
treatment (NNT= 10‐12 over 12‐52 weeks) . If benefits occur, they should be seen within 3 to 6 months. 7
What About the Long‐Term Benefit? • Impact on long‐term outcomes, disability & institutionalization, is not clear. • AD2000 Study: Only nonpharmaceutical industry sponsored trial of cholinesterase inhibitors. [n=566 run‐in, 486 randomized; duration up to 5 years] Found no significant benefit of donepezil compared with placebo for the two primary endpoints: o Entry to institutional care o Progression of disability 8
Cholinesterase Inhibitors There is no evidence that one cholinesterase inhibitor is more efficacious than the 9 (grade 2B)
another o Donepezil, galantamine, and rivastigmine appear to have similar efficacy & similar adverse effects, however independent comparative trials among the acetylcholinesterase inhibitors are lacking. ARICEPT
• Donepezil o Initial dose: 5 mg once daily. If well tolerated, ↑ dose to 10mg once daily after at least 4 to 6 weeks (maximum dose is 10 mg daily). [Dose at HS or with food.] •
REMINYL
Galantamine (ER) o Initial dose: 8mg once daily in the morning, preferable with food. After 4 weeks, ↑ dose to 16mg once daily (initial maintenance dose). If initial maintenance dose is well tolerated, consider ↑ to 24mg once daily after at least 4 weeks (maximum dose is 24mg daily). EXELON
Cholinesterase Contraindications • Uncontrolled/severe asthma or severe COPD • Cardiac conduction adnormalities (special caution if on beta‐blockers) • Peptic ulcer disease • Urinary obstruction • Seizure history • Concurrent use of anticholinergic medications (can negate any benefit) • Angle‐closure glaucoma • Sick sinus syndrome • Left bundle‐branch block 13
N‐methyl‐D‐aspartate (NMDA) Receptor Antagonist Generally better tolerated than the cholinesterase inhibitors, but is not effective in mild to 14
moderate disease. •
•
EBIXA Memantine Initial dose: 5 mg once daily, in the morning. If well tolerated, ↑ in weekly increments of 5mg to maintenance dose of 10mg BID. Combination Therapy: Cholinesterase Inhibitor + Memantine Combination therapy is rational, as the medications have different mechanisms of action, & appear to be safe, but there is insufficient evidence to recommend for or against this 15 (grade 2B)
combination . The evidence is conflicting. Some studies indicate that individuals with moderate to severe AD dementia (vs mild to moderate) may benefit from combination 16 17 18 (DOMINO)19
20 21
therapy ; however a systematic review that included two of these studies concluded that the addition of memantine to an acetylcholinesterase inhibitor provides no 22
additional benefit on cognitive, behavioural, functional, or global measures. Adding memantine to donepezil when an individual progresses to moderate to severe (DOMINO)23, 24, 25
Alzheimer’s is not likely to offer any benefit.
Pg 9
Dementia & Cognitive Impairment www.rxfiles.ca 26 27 28 29 30
Potential Adverse Events Associated with Treatment ARICEPT
REMINYL
EXELON
Cholinesterase Inhibitors (donepezil , galantamine , rivastigmine ) • Many individuals experience adverse effects (NNH=12). Most common: nausea, loss of appetite, vomiting & diarrhea. The incidence of adverse events ↑ with dose ↑. • The adverse effects become more tolerable over a few weeks. Slow titration, administration with food, & an antiemetic may improve tolerability. • Possible adverse effects include: nausea & vomiting, diarrhea (~10%), anorexia, weight loss (~3%), insomnia, agitation (initially), cholinergic effects (e.g. incontinence, stomach, bradycardia, syncope, falls, nightmares), ↑ risk of GI bleed (due to ↑ central & peripheral cholinergic simulation ‐ Particularly in individuals with ulcer disease or those taking anti‐inflammatories), QT prolongation (<1% incidence) – donepezil & galantamine. Behaviour disturbance may also occur. EBIXA
Memantine Use with CAUTION in patients with cardiovascular disease or a history of seizures • Possible adverse effects include: dizziness, constipation, confusion, insomnia, headache, hypertension, inner & motor restlessness, akathisia, nausea; QT prolongation (<1% incidence) 31
Balancing the Risks vs the Benefits Cholinesterase inhibitors produce, on average, small improvements in measures of cognition & ADL o NNT “improved” on a global assessment scale (CGIC or CIBIC+) = 12 o NNT 4‐point or greater improvement on ADAS‐cog = 10 o NNH adverse event = 12 {Note: trials done is more healthy patients, & benefits may be less in real life.} • May slow progression by months, not years • Not all individuals benefit, but some may “feel better” • Many cannot tolerate the side effects – marginal benefits may be outweighed by harms that ↓ quality of life When Do the Risks Likely Outweigh the Benefits? • In the frail elderly, especially with multiple co‐morbidities • Problematic urinary incontinence • Individuals with significant weight loss • Individuals with significant behaviour problems (aggression, agitation) • Individuals with financial restrictions (e.g. if you had $20 to spend, where would it best be spent?) • Individuals with severe dementia When to Follow‐up After the Initiation of Treatment • At 1 month: follow‐up to assess for adverse events & a possible increase in dose • At 3 months: assess for cognitive effects – is there any benefit? o Consider continuing if improvement is noted either on bedside testing (MMSE) or by the family/caregivers (FAQ). o Consider discontinuation if there has been no improvement. • Every 6 months afterward Remember: cholinesterase inhibitors are a symptomatic treatment & not disease‐modifying. Administer for 8 weeks at the recommended or maximum tolerated dose & then review the individual's response with the family and/or caregivers. How Long Should Cholinesterase Inhibitors be Used? 32 33
When Should a Cholinesterase Inhibitor be Discontinued? • Cholinesterase inhibitors can be continued indefinitely, but evidence of benefit in advanced stages is limited (trials were 6 months in duration). •
Because of known side effects & drug costs of continuing therapy, discontinuation of cholinesterase inhibitors should be considered & balanced against possible worsening of (grade 2B)
cognitive function & greater functional impairment.
It is suggested that cholinesterase inhibitors be discontinued when the following are relevant: o The individual, caregiver, or substitute decision‐maker decides to stop cholinesterase inhibitors after being informed of the risks & benefits of continuation & discontinuation. o The individual is non‐adherent & continued prescribing would be useless. o The comorbidities of the individual make continued use of the agent unacceptably risky or futile (e.g. terminal illness). o The individual’s rate of cognitive, functional, or behavioural decline is greater on treatment compared with that before being treated. o The individual demonstrates a poor response to the medication (both MMSE & FAQ decline over 6 month period). o The individual’s dementia progresses to a stage where there would be no meaningful benefit from continued therapy (e.g. Global Deterioration Scale stage 7). At this advanced stage of the disease, individuals are no longer able to manage basic ADL (e.g. toileting, dressing) & are forgetting their own personal history. o The cost of the medication becomes problematic (e.g. EDS coverage lapses once MMSE <10 in Saskatchewan). o The individual experiences intolerable side effects that are definitely or probably related to the cholinesterase inhibitor. This may include: • Aggression, behaviour disturbance, and/or poor sleep • Nausea with weight loss • Bradycardia • GI adverse events (GI bleed; bothersome nausea/diarrhea) Pg 10
Dementia & Cognitive Impairment Stopping a Cholinesterase Inhibitor When it has been decided that treatment with a cholinesterase inhibitor be stopped, it is suggested that the dose be tapered before stopping the agent. Caregivers should be warned that discontinuation of pharmacotherapy may cause cognitive & behavioural decline. Taper over 2 to 4 weeks. For example, consider reducing the donepezil dose from 34
10 mg to 5 mg once daily for four weeks before stopping it. The medication may be restarted if there is a temporal relationship between the discontinuation of the medication & sudden deterioration by the individual. www.rxfiles.ca Can Dementia be Prevented? 46 ‐ continued 47 48
Gingko Two RCTs: 1) Solomon 2002 ‐ 230 cognitively healthy older adults after 6 weeks did not show a significant difference in any cognitive outcome measured; 2) Dodge 2008 ‐ 118 patients over 42 months also found no significant change in cognitive decline between the gingko & 49
50
placebo groups. Ginkgo biloba did not prevent dementia in one prospective trial Vitamins & Fatty Acids RCTs have assessed the use of various vitamins and fatty acids for the prevention of cognitive If discontinued because of perceived lack of effectiveness, it is recommended that the 51
, vitamin E (n = 6377, study duration nearly patient be monitored over the next 1 to 3 months for evidence of an observable decline. If decline. Vitamin B6 (n = 76, study duration 12 wk)
52
53
(grade 2C) 35 36 37
10 yr)
, folic acid (n = 24, study duration 4 wk)
& the omega‐3 fatty acid EPA–DHA this occurs, it is suggested that reinstating therapy be considered. Symptoms 54
38
(eicosapentaenoic acid– docosahexaenoic acid; n = 302, study duration 6 mo) have all been may not be fully reversible if there is a delay in restarting pharmacotherapy. studied, & none showed evidence of preventing cognitive decline. There is some evidence that vitamin E may in fact be associated with increased morbidity & mortality. 39
Can Dementia be Prevented? There is no consistent evidence of benefit for any pharmacologic agent in preventing cognitive decline in healthy older adults. Anti‐inflammatories A study conducted over 3 years investigated the use of naproxen & celecoxib among 2500 patients & found a marginal decline in memory with use of the medications; global 40
summary scores were 0.05 standard deviations lower (p = 0.02) in the treatment arm. However potential harms (e.g. GI bleeds) are also known to be significant. Cholinesterase Inhibitors Cholinesterase inhibitors do not prevent the progression of mild cognitive impairment 41
(MCI) to dementia. 42 43 44
Dehydroepiandrosterone (DHEA) Three RCTs investigated the use of DHEA in a total of 317 patients. Follow‐up was from 6 weeks to 1 year. None of the 3 studies showed a statistically significant improvement in cognitive function with the use of DHEA supplements. Estrogens Studies investigating estrogen therapies have shown evidence of a ↓ in memory & cognitive function, & an ↑ in incident dementia (hazard ratio 1.8, 95% confidence interval [CI] 1.2 to 2.6). The WHIMS was a RCT of estrogen + progestin (n = 2229) versus placebo (n = 2303) for prevention of dementia in women aged ≥65 years. Use of estrogen for a mean of 4 years was associated with a relative risk of 2.05 (CI, 1.21–3.48) for dementia 45
during the study period. There is however some controversy about these findings – some might debate that the ‘type’ or ‘formulation’ of estrogen used plays a role. (i.e. Would bioidentical hormones produce better results versus synthetic or equine derivatives? Would topical formulations, which some consider “safer” than oral formulations, produce better results?) Non‐Pharmacological Interventions • The evidence for physical activity in preventing cognitive decline is weak. One RCT investigating resistance training in healthy older adults showed improvement in cognitive 55
outcomes. • Formal cognitive training exercises may have a benefit in preventing cognitive decline. There is consistent evidence that cognitive training using formal programs is effective at 56 57 58
preventing cognitive decline based on 3 RCTs. 59
Modifiable Risk Factors A 2011 meta‐analysis identified 7 potentially modifiable risk factors for AD & calculated a population attributable risk or PAR (the percent of cases attributable to a given factor) & CI for each in the United States: o Cognitive inactivity or low educational attainment (PAR = 7.3% [CI, 4.4–10.3]) o Depression (PAR = 14.7% [CI, 9.6–20.3]) o Diabetes mellitus (PAR = 3.3% [CI, 1.5–5.4]) o Midlife hypertension (PAR = 8.0% [CI, 2.2–15.1]) o Midlife obesity (PAR = 7.3% [CI, 4.3–10.8]) o Physical inactivity (PAR = 21% [95% CI, 5.8–36.6]) o Smoking (PAR = 10.8% [CI, 3.0–19.8]) There may be additional modifiable risk factors, such as wearing a helmet to prevent head injury, not included in the above list. Pg 11
ANTICHOLINERGICS: Reference List of Drugs with Anticholinergic Effects 1, 2, 3, 4 Julia Bareham BSP © www.RxFiles.ca Oct 2014 WHENEVER POSSIBLE, AVOID DRUGS WITH HIGH ANTICHOLINERGIC ACTIVITY IN OLDER ADULTS (>65 YEARS OF AGE) Antibiotics Antimuscarinics
ampicillin 5 *ALL AVAILABLE AS cefoxitin χ 5 GENERIC clindamycin 5 gentamicin (Oint & Sol’n NIHB covered) 5 piperacillin χ ⊗ 5 vancomycin ⊗ 5 TCA
Antidepressants
amitriptyline
clomipramine
desipramine
doxepin
imipramine
nortriptyline
ELAVIL
ANAFRANIL
NORPRAMIN
SINEQUAN
TOFRANIL
AVENTYL
‐less anticholinergic effects than amitriptyline & imipramine SURMONTIL
citalopram œ
escitalopram œ
fluoxetine
fluvoxamine
paroxetine
sertraline
œ
CELEXA
5
CIPRALEX χ W 5
PROZAC
5
LUVOX
5
PAXIL
ZOLOFT
5
bupropion œ
desvenlafaxine
duloxetine
maprotiline
mirtazapine œ
moclobemide œ
phenelzine
trazodone
œ
venlafaxine œ
WELLBUTRIN, ZYBAN 5
PRISTIQ χ ⊗ 5
CYMBALTA 5
LUDIOMIL
5
REMERON
5
MANERIX
5
NARDIL
5
TRAZOREL
5
EFFEXOR
5
6
SSRI
-----------------------------------------------------------------------------------------------
6
In the elderly, citalopram
& sertraline are the usually preferred SSRIs. ZOLOFT
Antiemetics/Antivertigo dimenhydrinate
meclizine
promethazine
scopolamine
Other
amantadine
benztropine mesylate
bromocriptine
carbidopa/levodopa œ
entacapone
ethopropazine
pramipexole
procyclidine
selegiline
trihexyphenidyl
SYMMETREL 5
COGENTIN
6
PARLODEL 5
SINEMET 5
COMTAN 5
PARSITAN
6
MIRAPEX 5
KEMADRIN
6
ELDEPRYL W 5
ARTANE
6
GRAVOL OTC
BONAMINE
PHENERGAN OTC χ ⊗
TRANSDERM V OTC ⊗
Antihistamines/Antipruritics 6
6
6
6
brompheniramine COUGH&COLD PRODUCTS OTCχ 6
chlorpheniramine CHLOR‐TRIPOLON OTCχ 6
cyproheptadine
PERIACTIN OTCχ ⊗ 6
OTC
dimenhydrinate
GRAVOL
6
diphenhydramine
BENADRYL OTCχ
6
hydroxyzine
ATARAX
6
pyrilamine
MIDOL, PAMPRINOTCχ⊗6
trimeprazine ◊
PANECTYL
⊗ 6
Preferred Alternatives: certirizine REACTINE χ, fexofenadine ALLEGRA χ, loratidine CLARITIN χ. 5
5
5
5
atenolol
captopril
chlorthalidone
digoxin
diltiazem œ
diospyramide
furosemide
hydralazine
isosorbide ◊
metoprolol œ
nifedipine
quinidine
triamterene
TENORMIN
CAPOTEN
5
5
GENERIC ONLY
5
LANOXIN, TOLOXIN 5
CARDIZEM
5
RYTHMODAN
LASIX
APRESOLINE
ISORDIL
LOPRESOR
ADALAT
6
5
5
5
5
5
5
5
GENERIC ONLY χ ⊗
DYRENIUM
metoclopramide
nizatidine
prochlorperazine
ranitidine
6
6
6
Opioids
meperidine
DEMEROL*Not for chronic use 6
codeine
( on controlled release only, , inj & liquid) 5
fentanyl
DURAGESIC 5
hydromorphone œ DILAUDID,
HYDROMORPH CONTIN on CR only 5
morphine œ
STATEX, M.O.S., KADIAN 5
oxycodone
SUPEDOL, OXY IR
OXYNEO ⊗
5
tramadol œ
ULTRAM, RALIVIA, TRIDURAL,
ZYTRAM XL χ ⊗
5
Respiratory Meds
6
6
6
6
6
6
6
5 if used short term
ZANTAC OTC & Rx 5
‐low anticholinergic activity if adjusted for renal function IMURAN
NEORAL 6
6
6
6
Baclofen is the preferred agent of the above listed muscle relaxants however, it does display moderate to high anticholinergic activity. fluticasone/salmeterol
theophylline
5 if used short term
MAXERAN
5
AXID
5
STEMETIL
LIORESAL ( on intrathecal only) 5
FLEXERIL ROBAXIN OTCχ ⊗
NORFLEX OTC χ ⊗
ZANAFLEX Preferred Alternatives: acetaminophen χ, NSAIDs (e.g. ibuprofen, naproxen) Immunosuppressants
Antispasmotics baclofen
cyclobenzaprine
methocarbamol
orphenadrine
tizanidine
Gastrointestinal Agents
belladonna
GENERIC ONLY χ ⊗
chlordiazepoxide/clidinium LIBRAX χ ⊗
cimetidine
TAGAMET
dicyclomine
BENTYLOL ⊗
diphenoxylate/atropine
LOMOTIL ⊗
famotidine œ
PEPCIDOTC & Rx 5
loperamide
IMODIUMOTC
azathioprine
cyclosporine
Preferred Alternatives: divalproex EPIVAL, gabapentin NEURONTIN, lamotrigine LAMICTAL. dicyclomine
FORMULEX, BENTYLOL ⊗
glycopyrrolate
ROBINUL χ ⊗
hyoscine butylbromide
BUSCOPAN ⊗
5
5
5
5
5
5
5
5
5
5
5
Avoid long‐ & ultra‐short acting agents in the elderly. Preferred Alternatives: bisacodyl χ, PPIs , domperidone; ranitidine if ≤150mg/day Antiseizure Drugs TEGRETOL
EPIVAL
TRILEPTAL ⊗
DEPAKENE
Muscle Relaxants
XANAX half‐life: ~12 hr
LIBRIUM half‐life: ~100 hr ⊗
RIVOTRIL half‐life: ~34 hr
TRANXENE half‐life:~100 hr ⊗
VALIUM half‐life: ~100 hr
DALMANE half‐life:~100 hr ⊗
ATIVAN half‐life: ~15 hr
VERSED half‐life: ~3 hr χ ⊗
SERAX half‐life: ~8 hr
RESTORIL half‐life: ~11 hr
HALCION half‐life: ~2 hr
Cardiovascular Agents
aripiprazole œ
ABILIFY 5
asenapine ◊ SAPHRIS (-BPAD) ⊗ LARGACTIL
6
chlorpromazine
clozapine
CLOZARIL W
6
flupentixol
FLUANXOL
6
fluphenazine
MODITEN
6
haloperidol œ
HALDOL
5
loxapine
LOXAPAC
6
lurasidone ◊ LATUDA χ ⊗ methotrimeprazine
NOZINAN
6
olanzapine
ZYPREXA W
6
paliperidone
◊
INVEGA (⊗ on injection only) 5
pericyazine
NEULEPTIL
6
perphenazine
TRILAFON
6
pimozide
ORAP
6
pipotiazine
◊
PIPORTIL
5
quetiapine
SEROQUEL
6
risperidone œ
RISPERDAL (⊗ on injection only) 5
thioproperazine ◊
MAJEPTIL χ
6
thiothixene
NAVANE
6
trifluoperazine
STELAZINE
6
ziprasidone œ
ZELDOX 5
zuclopenthixol ◊
CLOPIXOL ⊗
6
carbamazepine
divalproex œ
oxcarbazepine
valproic acid œ
alprazolam
chlordiazepoxide
clonazepam
clorazepate
diazepam
flurazepam
lorazepam œ
midazolam
oxazepam œ
temazepam œ
triazolam
(Clonazepam ok, if long‐acting required e.g. chronic anxiety) Antipsychotics
-----------------------------------------------------------------------------------------------
CELEXA
Benzodiazepines
ENABLEX 6
TOVIAZ χ
6
URISPAS χ
6
MYRBETRIQ χ ⊗ 6
DITROPAN ( on CR only) 6
VESICARE 6
DETROL 6
TROSEC 6
Antiparkinsonian
6
6
6
6
6
6
trimipramine
darifenacin
fesoterodine
flavoxate
mirabegron ◊
oxybutynin
solifenacin
tolterodine l‐tartrate
trospium
5
5
Inhaled (COPD) Meds aclidinium bromide TUDORZA GENUAIR χ ⊗ ipratropium
ATROVENT
5
glycopyrronium SEEBRI BREEZHALER tiotropium
SPIRIVA 5
TO MINIMIZE SYSTEMIC EFFECS OF INHALATIONAL MEDS: AVOID OVERUSE, USE AEROCHAMBER FOR IPRATROPIUM, EXTRA CAUTION WITH “MIST” FORMULATIONS IN SOME COUNTRIES. buspirone ◊
colchicine
dipyridamole
ADVAIR 5
THEOLAIR, UNIPHYL 5
Miscellaneous
ketotifen ophthalmic
lithium
BUSPAR ⊗
GENERIC ONLY
PERSANTINE,
AGGRENOX ZADITOR ⊗
CARBOLITH,
DURALITH
GENERIC ONLY χ ⊗
COUMADIN
pancuronium
warfarin œ
Moderate/High anticholinergic activity Low anticholinergic activity 5
5
5
5
5
5
5
_______ = Possible preferred alternatives
œ = Denotes agents with anticholinergic activity that may be better tolerated than others. Whenever possible, anticholinergic drugs should be avoided, & the preferred agents used.
◊ = Unable to confirm anticholinergic activity (black font)
= EDS (exception drug status) in Saskatchewan
χ = non‐formulary in Saskatchewan
= prior approval NIHB W=covered by NIHB
⊗ = not covered by NIHB
AChEI = Acetylcholinesterase Inhibitor (eg. Donepezil
ARICEPT
, galantamine REMINYL, rivastigmine EXELON) CR = Controlled Release Formulation
PPI = Proton Pump Inhibitor (eg. rabeprazole)
OTC = Over‐the‐counter
5 = Saskatchewan Health finds co‐administration of this agent with a AChEI acceptable
6 = If patient is currently on this medication, Saskatchewan Health will NOT cover AChEI
111
Pg 12
Dementia: Behavioural & Psychological Symptoms1 2 The behavioural & psychological symptoms of dementia (BPSD) can create a significant caregiver challenge. BPSD of varying degrees of severity are present in more than 90% of individuals with 3
dementia. Common Behavioural & Psychological Symptoms of Dementia Aggression (both verbal & physical)* Hostility Psychomotor hyperactivity
Intrusiveness Agitation Repetitive behaviours Nocturnal restlessness Resistive (e.g. to personal Anger, Irritability (screaming) care) Paranoid behaviours Apathy Sexual disinhibition Psychosis (includes Depression Emotional lability, Disinhibition hallucinations, delusions & Vocalizations (repetitive) paranoia) Wandering, Pacing Hoarding *Physical aggression may include: biting, destroying property, grabbing, hitting, kicking, pushing, scratching, spitting, throwing items. www.rxfiles.ca MEDICAL Triggers MEDICATION Triggers Ì Medication that Approach to Managing BPSD must be tapered when discontinuing Identify whom the behaviour is bothering (the individual, caregivers, other residents) ‰ Assess for any triggering factors (not an exhaustive list): Distress PSYCHOLOGICAL Triggers Fear of Danger Feeling Abandoned Loss of Autonomy or Control Misinterpretation Paranoia “Bad Company” (not liking who is around) Boredom ENVIRONMENTAL Confusing Surroundings Triggers Excessive Demands Lack or Change of Routine Loneliness Low Lighting Noise / Sounds / Certain Music Acetylcholinesterase Inhibitors Ì
(e.g. donepezil ARICEPT) Anticholinergic Medications (see page 24A) Ì Anticonvulsants (e.g. carbamazepine, phenytoin) Ì Anti‐Parkinson Medications Ì (e.g. levodopa/carbidopa SINEMET) Benzodiazepines Ì (e.g. lorazepam ATIVAN) Fluoroquinolones (e.g. ciprofloxacin, norfloxacin) H2 Antagonists (e.g. ranitidine, cimetidine) Lithium Opioids Ì (e.g. codeine, morphine) Substance Abuse (e.g. alcohol, stimulants, others) Systemic Corticosteroids Digoxin (especially high doses) Ì & many others, see RxFiles anticholinergic list. ‰ Determine if the symptom requires treatment. •
Some behaviours or psychological symptoms may not require treatment if they are not problematic, or treatment risks may outweigh potential benefits. o It may be appropriate to allow for wandering within limits. Locked neighbourhoods (unit or wing) in long‐term care homes may allow for this behaviour if an individual is not wandering into the rooms of other residents & disturbing them. o Hallucinations & delusions may not require treatment if they do not cause distress to an individual. For example, if an individual is hallucinating that a family member is present & he/she is pleasantly conversing with the “imagined” family member, treatment of the hallucination would not be required. or unprovoked (antecedent), details of the specific behaviour such as if it was verbal, physical or sexual (behaviour), & what happened after the behaviour (consequence). ƒ Look for patterns after recording the behaviour several times. •
Infection (e.g. pneumonia, UTI) Metabolic (e.g. hyponatremia) Nocturia Pain* Urinary Retention *Undetected pain or discomfort are common in individuals with dementia, & is estimated to occur in up to 83% of individuals.7 Pain is often poorly recognized & undertreated due to an individual’s difficulty in communicating his/her needs.8 Alternately, some complaints & request for analgesics could be attention seeking behaviour. See Section 22 for more information on assessing pain. ‰ Document the target symptom. • Be specific o A number of validated standardized assessment tools are available to assist with the tracking, assessment, & documentation of behaviours such as: the Cohen Mansfield Agitation Inventory, Dementia Observation Scale, & Behaviour Pattern 4
Record. • Identify what causes the behaviour & what makes it better or makes it go away o The ABC approach is useful: A – Antecedents B – Behaviour C – Consequences 5 6 ƒ Document what happened before the behaviour such as morning care routine, meal, B12/Folic Acid Deficiency Constipation or Fecal Impaction Hunger or Thirst Hypercalcemia Hypothyroidism Non‐Pharmacologic Interventions vs Pharmacologic Treatment ‰
Use non‐pharmacological measures whenever possible. Non‐pharmacologic interventions have often been shown to be more effective than pharmacologic treatment for dementia‐related behavioural problems & should be attempted first, whenever possible. They also address behavioural triggers & avoid the problems associated with pharmacologic interventions (e.g. adverse events, drug 9
interactions, & limited efficacy). If the individual/resident or caregivers are at risk of harm or danger, sole reliance on non‐
pharmacological measures may not be appropriate, & pharmacologic options may be required. However, with ongoing efforts to train caregivers & staff, less reliance on medications can be realized over time. Pg 13
Dementia: Behavioural & Psychological Symptoms Non‐Pharmacologic Treatments What are the Pharmacologic Options? 10
Non‐Pharmacological Treatment for PSYCHOLOGICAL Triggers • Show a warm, kind, matter‐of‐fact manner • Make eye contact (if culturally appropriate) • Use the individual’s name • Provide simple step‐by‐step instructions • Ask questions with limited choices such as “Would you like water or milk?” rather than “What •
•
•
•
•
•
•
•
www.rxfiles.ca would you like to drink?” Avoid social isolation (but observe the impact of various social environments on mood) Facilitate or arrange for spiritual care when appropriate Allow the individual to make decisions whenever possible Reassure & redirect the individual Avoid frequent corrections, e.g. “Please do this,” instead of “Don’t do this” Stay calm and patient when speaking & avoid tense body language Don’t argue with an individual Don’t talk about the individual as if he/she is not there or speak ill of other residents in their absence (remember, some residents have excellent hearing) Treatment options for BPSD are dependent upon the symptom(s) that an individual is experiencing. When pharmacological interventions are initiated, ensure that a clear goal of therapy has been identified. Also ensure that a monitoring plan & evaluation plan of progress are clearly defined. The following sections explore the various treatment approaches for both the behavioural disturbances associated with dementia, & the psychological symptoms of dementia. Anxiety Use non‐pharmacological interventions whenever possible & minimize provocation. Anxiety may be chronic in nature or may be intermittent & caused by anxiety provoking situations. • For CHRONIC anxiety: o Consider antidepressant therapy if anxiety is secondary to depression or very chronic in nature (this is addressed in a following section entitled “Depression”). CELEXA
ZOLOFT
ƒ Antidepressants with anxiolytic properties: citalopram , sertraline , EFFEXOR XR
DESYREL
MANERIX
venlafaxine , trazodone , moclobemide . 11 12
Non‐Pharmacological Treatment for ENVIRONMENTAL Triggers • Encourage the individual to use his/her glasses or hearing aids (caution in noise sensitive •
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•
•
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•
individuals) Assist with appropriate physical exercise such as a walk Provide regular daily routine, activities & structure Provide a comfortable, familiar living environment (e.g. obtain pictures, ornaments from home, pet therapy with a familiar animal) Engage the individual in simple daily activities that he/she is able to do Avoid overstimulation (noise, TV, crowds) Refer individuals to adult day care programs if needed and as available Consider aromatherapy or music therapy (find out what type of music the individual enjoys) Other useful activities to consider: gardening, music & dancing, art, interactions with a pet, group activities (e.g. singing, crafts) 13
Non‐Pharmacological Treatment for MEDICAL Triggers • Offer food & drink • Treat symptoms such as pain, constipation, urine retention, nausea, dyspnea, if present • Evaluate & treat endocrine & metabolic disorders (blood sugar, thyroid, etc) • Evaluate & treat infections according to goals of care (pneumonia, UTI, dental caries) • Evaluate & treat cardiovascular disorders according to goals of care 14
Non‐Pharmacological Treatment for MEDICATION Triggers • Discontinue medications that may be contributing to the BPSD, when possible (taper or ↓ dose) For more information on the management of specific symptoms related to dementia, see RxFiles: An Introduction to the Various Types of Dementia, Their Management & Treatment BUSPAR
o Buspirone : 10 to 30mg per day, divided BID to TID (possibly as high as 60mg/day) ƒ Has a delayed onset of ~3 weeks when used for chronic anxiety (may limit its usefulness) ƒ Compared to benzodiazepines, buspirone is less sedating, has fewer drug interactions, causes less withdrawal & less impairment of motor function ƒ The best response will be achieved in individuals who are benzodiazepine naïve o B Clonazepam RIVOTRIL
: 0.125 to 2mg per day, divided BID to TID ƒ Long‐acting benzodiazepine (half‐life ~34 hours) ƒ Long‐acting benzos are not frequently recommended in older adults except for in certain circumstances, including severe generalized anxiety ƒ See cautions below (e.g. falls, cognitive impairment, disinhibition) • For INTERMITTENT anxiety: o Use agents short‐term (<1 month while waiting for antidepressant to work) & only as‐needed o Intermediate‐acting benzodiazepines may be most appropriate if used short‐term for anxiety states or before planned anxiety provoking situations (e.g. bathing, dental work) ATIVAN
ƒ Lorazepam : 0.5 to 1mg prn, up to TID (available as a sublingual tablet) SERAX : 10mg BID to TID may be a suitable alternative ƒ Oxazepam Benzodiazepine CAUTIONS ‐ Can cause sedation, ataxia (lack of muscle control during voluntary movements), altered sleep architecture, night wandering, motor impairment, cognitive impairment, confusion, paradoxical excitation, disinhibition, falls. ‐ Withdrawal symptoms can occur when discontinued, therefore tapering required Ì. Pg 14
Dementia: Behavioural & Psychological Symptoms www.rxfiles.ca 15 16
Apathy Apathy is defined primarily as a loss of motivation & reduced emotional reactivity. Treatment with external activity & environmental measures likely most effective. Depression Continued • Serotonin‐Norepinephrine Reuptake Inhibitors (SNRIs) EFFEXOR XR o Venlafaxine : 37.5 to 150mg daily ƒ The XR capsule can be opened & sprinkled on applesauce while maintaining its 24 hour action – do not chew spheres/granules. ƒ Adverse events are similar to those of SSRIs, but with more common GI events, & may ↑ blood pressure. High risk of withdrawal syndrome; gradual tapering important. Pharmacotherapy may be an option, but some agents such as antidepressants may worsen apathy. Occasionally, stimulants may be helpful, but present an array of problematic adverse effects. Cholinesterase inhibitors may also help somewhat (anecdotal). RITALIN
o Methylphenidate : 5 to 20mg BID to TID (Off‐label use: depression; the recommended initial dose is 2.5mg in the morning) ƒ
Common adverse events reported: ↑ blood pressure, ↓ appetite/weight loss, dizziness, sleep disturbance, irritability, delusions, restlessness, agitation, ↑ heart rate. This medication may also present diversion concerns. Depression Pharmacologic options should not be used to treat mild depression, & should be reserved for moderate to severe depression. These agents may improve depression, depression associated agitation, emotionality & irritability. They may also improve some behaviours such as disinhibition. Antidepressant medications may worsen apathy in some individuals. Allow >6 weeks for adequate trial at an adequate dose. Start low, go slow, but go! • Selective Serotonin Reuptake Inhibitors (SSRIs) ‐ first‐line for depression, best tolerability17 •
CELEXA
o Citalopram : 10 to 20mg daily *CAUTION: doses >20mg are not recommended due to the risk of QT prolongation (see Section 7) ƒ Citalopram has the best evidence for reducing agitation & aggression18, 19 CIPRALEX
o Escitalopram : 5 to 10mg daily *CAUTION: doses >10mg are not recommended due to the risk of QT prolongation (see Section 7) CIPRALEX MELTZ ƒ Escitalopram also available in an orally disintegrating formulation
ZOLOFT
o Sertraline : 25 to 100mg daily AVENTYL
o Nortriptyline : 10 to 50mg at bedtime *likely the best tolerated TCA in older adults – least hypotensive TCA & less anticholinergic than 3° TCAs (e.g. amitriptyline) NORPRAMIN
o Desipramine Tricyclic Antidepressants (TCAs) o If possible, avoid 3° TCAs due to their greater anticholinergic activity (i.e. amitriptyline, clomipramine, doxepin >6mg/day, imipramine, & trimipramine) Possible adverse events include: hypotension, blurred vision, urinary hesitancy, QT prolongation (less likely with nortriptyline – see Section 7) • If dry mouth is a problem, consider a “saliva substitute” product to minimize this adverse effect • Others WELLBUTRIN SR/XL o
Bupropion : 100 to 150mg BID (SR) or 150 to 300mg daily (XL) ƒ May help activate an individual with withdrawal or psychomotor retardation. ƒ Lowers seizure threshold (dose‐dependent; low risk when dose ≤ 400mg/day [0.4%]). o
Mirtazapine o
Moclobemide REMERON
: ≤7.5 to 30mg at bedtime (can start as low as 3.75mg to minimize adverse effects) ƒ Consider for individuals with co‐morbid anorexia, anxiety, or sleep difficulties. ƒ Orally disintegrating formulation available (if difficulty swallowing). LUVOX
o Fluvoxamine : 25 to 100mg daily at bedtime : 25 to 150mg daily at bedtime (sedating, many drug interactions) ƒ
ƒ
MANERIX
: 100mg daily to 300mg BID May help with anxiety. Can cause restlessness/↑ stimulation. PROZAC
o If possible, avoid fluoxetine PAXIL
due its long‐half life & avoid paroxetine due to its anticholinergic properties. Both these agents have many drug interactions. May consider these options if they were previously effective. {Fluoxetine also available in liquid form commercially.} Possible adverse events to monitor for: nausea, vomiting, restlessness, falls, insomnia, weight loss, agitation (especially upon initiation), hyponatremia, bleeding (e.g. stroke, upper GI, bruising). Notes: ____________________________________________________________________________
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____________________________________________________________________________ Pg 15
Dementia: Behavioural & Psychological Symptoms Psychosis, Agitation & Aggression The pharmacologic treatment of behavioural disturbances in dementia is of limited efficacy & should be used after non‐pharmacologic interventions have been implemented, 20
if appropriate. Pharmacological interventions may be appropriate for PSYCHOSIS, AGITATION OR AGGRESSION if the behaviour: ‰ Is causing harm or significant distress to the individual themselves, caregivers or others living in the same home AND is persistent or recurrent ‰ Has not adequately responded to non‐pharmacological interventions (& an effort has been made to exhaust all possible non‐pharmacological measures) ‰ Is not due to reversible or treatable causes (e.g. a physical cause or medication‐
induced) ‰
The behaviour is moderate to severe (as opposed to mild) www.rxfiles.ca Potential Harms Associated with Atypical Antipsychotics: • ↑ weight, hyperlipidemia, hyperglycemia • Sedation, lethargy • Falls; postural hypotension • Confusion, agitation, delirium, akathisia (restlessness) Æ due to anticholinergic & anti‐
dopaminergic effects • Extrapyramidal effects (EPS): drooling, rigidity, stiffness, akinesia (a slowness or loss of normal motor function resulting in impaired muscle movement) • Tardive dyskinesia (involuntary, repetitive body movements) • Infections (respiratory & urinary tract) • Stroke ƒ The risk (odds ratio) is about 1.3 to 3.1.23 That is to say that an individual who is taking an atypical antipsychotic for BPSD is 1.3 to 3.1 times more likely to have a stroke as a result of the use of this class of medication. ƒ No one antipsychotic is considered to be safer than another in terms of stroke, however some studies have found that risperidone may have a greater risk of stroke. 24, 25, 26, 27 ƒ Higher doses, older age, a diagnosis of dementia (especially vascular dementia), & comorbid atrial fibrillation have been noted as risk factors for stroke.28 ƒ The risk remains elevated for ~20 months after the initiation of treatment.29 Remember to ask: “Is my patient’s/resident’s behaviour change possibly due to a drug or medical condition?” before asking for a drug to manage it. Antipsychotics • The effectiveness of antipsychotics for BPSD is modest, & clinical value is limited due to serious adverse events. • In BPSD trials, placebo response rates are often ~40%, reflecting the high rates of 21
spontaneous resolution & the value of psychosocial input in such trials. • The more severe the behaviour or symptom, the better the response to antipsychotics • Antipsychotics should not be routinely used long‐term for BPSD. Thus, they should be reviewed for possible taper & discontinuation every 3 months . • Both older (typical) & newer (atypical) antipsychotics have been studied in BPSD; atypical antipsychotics are often preferred to help manage BPSD (but not acute delirium). • The most commonly used atypical antipsychotics include: risperidone , olanzapine ZYPREXA
SEROQUEL
ABILIFY
CLOZARIL
, & quetiapine . Aripiprazole & clozapine may also be used. HALDOL
o Haloperidol is appropriate for acute delirium (discussed in more detail elsewhere.) ‰ Consider the balance of the potential benefits of treatment with an antipsychotic RISPERDAL
(e.g. may improve safety of the individual &/or others [family, staff]; may ↑ quality of life) 22
versus potential harms relative to alternative treatment. Discuss with the individual/resident &/or family. The use of antipsychotics for BPSD has received a lot of attention due to the concerns related to the overuse of this class of medication for the treatment of BPSD. There are some controversies regarding off‐label marketing of antipsychotics in dementia; however, antipsychotics have a valid role when behaviour challenges outweigh safety concerns. One is sometimes stuck with the harm of using vs the harm of not using. • Possible ↑ risk of mortality 30 31 32
This is a somewhat controversial issue. There are limitations & potential confounders with the available data that leave us uncertain of the magnitude of the harm. Keeping this in mind, it is sometimes suitable to prioritize quality of life over prolongation of life when treating BPSD. ƒ The risk of death is about 1.2 to 1.6 times higher in individuals who take antipsychotics versus those who do not (placebo group). ƒ The most common conditions associated with cause of death are: pneumonia, cardiac failure & cardiac arrest (related to QT prolongation – see page 7B). o The risk of cardiac death ↑ with ↑ dose (dose‐related) ƒ No one antipsychotic is considered to be safer than another in terms of death, although two cohort studies have reported that quetiapine has the lowest mortality risk, compared to risperidone & olanzapine.33 34 o Risperidone: reference (risk = 1) o Olanzapine: relative risk = 1.02 (95% CI 0.92 to 1.12)35; no difference36 (i.e. olanzapine & risperidone demonstrate no difference in risk of mortality) o Quetiapine: relative risk = 0.76 (95% CI 0.7 to 0.82)37; (0.81, 0.75 to 0.88)38 (i.e. risperidone, carries a 24% greater mortality risk compared to quetiapine, likely associated with the lower dosages of quetiapine used) ƒ Older age, male gender, severe dementia, & functional impairment are associated with a higher risk. Dose of the medication may also play a role for all antipsychotics, except quetiapine.39 o For risperidone, the hazard ratio is 1.35 for high dose (>1mg), & 1.19 for medium dose (0.5 to 1mg) 40 ƒ i.e. high dose risperidone users are at a 1.35x greater risk of mortality o For olanzapine, the hazard ratio is 1.26 for high dose (>5mg), & 1.19 for medium dose (2.5 to 5mg) 41 ƒ The risk remains elevated in the first 30 to 120 days, & possibly up to 2 years after the initiation of treatment. ƒ Stopping treatment has been associated with a reduction in mortality (DART‐AD). Pg 16
Dementia: Behavioural & Psychological Symptoms ‰ Start low, & go slow! Some tips to help minimize potential adverse events, & maximize the efficacy of the medication when initiating an antipsychotic for aggression, agitation or psychosis due to dementia: • The starting dose should be as low as possible. o The starting dose can be divided or timed according to the behaviour. For example, lunchtime dose for individuals exhibiting increased agitation toward the end of the day. o The dose can be titrated up, in small increments, every 1 to 2 weeks, depending on response. • Aim for an improvement in target symptoms, not resolution. o If a positive response occurs, it is usually evident within 2 weeks, but it may taker longer.
Atypical Antipsychotics Ì RISPERDAL • Risperidone : 0.25 to 2mg daily or divided BID o The only atypical antipsychotic with an official indication for use in BPSD. o At higher doses, it may behave more like a typical antipsychotic in terms of a higher incidence of extrapyramidal effects.42 •
ZYPREXA
Olanzapine : 1.25 to 7.5mg daily or divided BID o May be modestly effective for treating agitation, but generally not recommended in individuals with dementia.43 Olanzapine’s anticholinergic properties can be particularly problematic in older adults, also associated with rapid & significant weight gain (in some older adults), sedation, & hyperglycemia.44 •
SEROQUEL
Quetiapine : 12.5 to 100mg daily (may use as high as 150mg daily or in some situations 200mg daily). Higher doses can be split into two or more divided doses. o Of the atypical antipsychotics, quetiapine is the best option in individuals with Parkinson’s or Lewy Body Dementia due to the ↓ risk of EPS (e.g. less stiffness) compared to other atypicals. Monitor closely for adverse events. Reassess in 3 to 7 days after the initiation of treatment, & regularly afterward for adverse events. www.rxfiles.ca 45
With atypical antipsychotics, monitor for: • CNS depression: sedation, increased confusion or cognitive impairment. • Anticholinergic effects: dry mouth, constipation, urinary retention, blurred vision, delirium – especially with olanzapine & quetiapine. • Dizziness & postural hypotension: increases risk of falls – especially with risperidone & quetiapine. • Extrapyramidal effects (EPS/movement disorders): ↑ muscle stiffness or rigidity, dyskinesias, dystonias – occur more frequently with higher doses of risperidone. • Metabolic changes: not observed frequently in older adults, monitor weight & possibly A1C if co‐existing diabetes or impaired glucose tolerance. • Infection: antipsychotic use is associated with an increased incidence of infections, in particular urinary infections & pneumonia. Combination & prn use of Antipsychotics CAUTION: potential for overuse of prn or combination use. Regular scheduled dosing is generally preferred over prn "as needed" antipsychotics. There is no evidence for using a combination of two different antipsychotics. There is no evidence for combination therapies with antipsychotics for BPSD (i.e. no added benefit), but there is an ↑ risk of adverse events. To minimize the risk of combination therapy, optimize the dose of the antipsychotic, allow for an adequate trial period (~2 weeks). If there is no response, discontinue the agent & initiate a new agent. ‰ Regularly review for adverse events AND the need for continuing treatment. •
Review within 3 to 7 days after the initiation of an antipsychotic or a dose ↑ for both tolerability & adverse events AND review treatment every 3 months to query if the medication is still beneficial / needed. Consider stopping (by taper Ì) every 3 months. The What, Why & How of Antipsychotic Tapering Ì WHAT: Review antipsychotic use every 3 months, & consider trialing a taper. • Review the target behaviour, changes in function & significance of adverse effects at least Older adults are especially vulnerable to the adverse effects of antipsychotics, & these may every 3 months, & document in the chart/record. Try tapering the dose or stopping the outweigh any benefits. Adverse effects are generally dose‐related & can be minimised by antipsychotic every 3 months using a slow, gradual taper. keeping the dose as low as possible. • CATIE‐AD demonstrated the limited long‐term role atypical antipsychotics have in the treatment of BPSD (quetiapine vs risperidone vs olanzapine vs placebo). o 80% of participants stopped therapy by 39 weeks due to poor tolerability (based on time to discontinuation due to adverse effects, intolerability or death) o Consider routine reassessment in 3‐6months for both efficacy & tolerability ‰
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Dementia: Behavioural & Psychological Symptoms The What, Why & How of Antipsychotic Tapering Ì continued WHY: BPSD may be short‐term & diminish with time, especially when mild‐moderate; long‐term use of atypical antipsychotics may result in ↑ mortality. • Dementia & the BPSD will present uniquely in each individual. Some behaviours will decrease in severity & may completely resolve as the dementia progresses. • DART‐AD (n=165, age ~85, Alzheimer’s with MMSE ≈ 11; 2 arms: continuation of an antipsychotic after 3 months of use vs switch to placebo). o Results: No significant difference in survival at 12 months. o Stopping long‐term ≥ 3 months antipsychotics reduced mortality by ~25% at 2 years 71% vs 46% survival.
ƒ Survival at 2 years: 71% placebo group still alive vs 46% antipsychotic group; NNT for discontinuation = 4/2years (i.e. One person will avoid death for every 4 who were on an antipsychotic for at least 3 months & stopped, at 2 years) ƒ Survival over 2 to 4.5 years: 54% placebo group survived vs 38% antipsychotic group; NNT = 8 o BPSD outcomes: no statistical difference except verbal fluency better in patients who stopped at 6 months. www.rxfiles.ca 50
What about haloperidol? • Does not differ significantly in effectiveness from atypical antipsychotics • Should generally be avoided in older adults given the high risk of extrapyramidal adverse effects & ↑ mortality as the dose is ↑, compared to atypical antipsychotics • Low‐dose haloperidol (0.5mg BID to TID) has a role in the short‐term management of the acute symptoms of delirium (except in individuals with Parkinsonism of any cause) Typical antipsychotics appear to have a ↑ risk of tardive dyskinesia & neuroleptic malignant syndrome. Among typical agents, haloperidol has a ↓ risk of anticholinergic effects, ↓ sedation & minimal weight gain, but a ↑ risk of parkinsonism & akathisia (use low doses 0.25 to 51
2mg daily) 52
What about anticonvulsants (or mood stabilizers) for agitation or aggression? DEPAKENE
EPIVAL
TEGRETOL
There are many limitations to using valproate / divalproex , carbamazepine LAMICTAL
or lamotrigine for the treatment of BPSD: • Valproate: Current evidence does not support its use & problematic adverse effects ; Requires lab monitoring • Carbamazepine: Limited evidence, many drug interactions, problematic adverse effects; Requires lab monitoring • Lamotrigine: Evidence limited to case reports & case series; Risk of Stevens‐Johnson Syndrome 53
HOW: Reduce dose by 25‐50% every 1 to 2 weeks (may be ↓ over longer intervals [e.g. every 4 weeks]). • Ì Withdrawal of antipsychotics should be done gradually to avoid withdrawal symptoms (dizziness, nausea, vomiting, headache, tremors, insomnia & anxiety). Other Medications & Their Role in BPSD Monitor for recurrence of target symptoms or behaviours or the emergence of • Cholinesterase Inhibitors (donepezil ARICEPT, galantamine REMINYL, rivastigmine EXELON)
new ones. o Modest cognitive, functional & behavioural benefit (e.g. NNT=10 for a 4‐point or greater improvement on ADAS‐cog). Not all individuals will benefit.
o May help apathy (also hallucination & maybe delusionspost‐hoc analyses).
o Unlikely to help agitation & aggression (not better than placebo for agitation). 54
o May help in Lewy Body Dementia to decrease visual symptoms.
What about the risk of recurrence of symptoms upon discontinuation? The risk may be higher in individuals with previously severe symptoms &/or if discontinuation has caused recurrence before. A slow, gradual taper will allow for monitoring and early identification of the re‐emergence of the BPSD (especially if risk of harm to self or others), which can be addressed by increasing the medication back up to the previously effective dose (this may be lower than the original dose). While the discontinuation of the medication may not be successful, the result may be that the individual is taking a lower dose of the medication. 46 47
How Do the Antipsychotics Compare? Efficacy: risperidone has the most evidence for efficacy (aggression ≤1mg/day & psychosis 48, 49
≤2mg/day). Possible Adverse Events (all dose‐dependent): • Anticholinergic & cognitive adverse events: olanzapine, quetiapine > risperidone • EPS: risperidone (↑ EPS doses >2‐4mg/day ) > olanzapine > quetiapine • QT Prolongation: quetiapine >>> risperidone • Sedation: olanzapine, quetiapine (lower doses of quetiapine are more sedating) > risperidone • Tardive Dyskinesia: risperidone > olanzapine > quetiapine • Weight Gain: olanzapine > quetiapine > risperidone • Memantine EBIXA
o May help agitation, irritability, disinhibition & psychosis, however the evidence is not rigorous 55 56 See Section 26 for more information on cholinesterase inhibitors & memantine
Sexually Inappropriate Behaviour • Assess for medical reasons (e.g. UTI) & any drug causes (e.g. lorazepam, dopamine agonists). Remove disinhibiting drugs including benzos & alcohol. • Treatment: Behavioural intervention 1 : redirection, distraction, avoiding stimulants o Limited data on drug treatment (SSRIs, antipsychotics, cholinesterase inhibitors) See RxFiles Hypersexuality Chart st
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RxFiles
www.RxFiles.ca - Oct 2014
A Crawley BSP, SHR Pharmacy Resident; L Regier BSP; L Kosar BSP, MSc; B Jensen BSP; J Bareham BSP MSc
References – Cholinesterase Inhibitors Newsletter – Oct 2014 ‐ www.RxFiles.ca 1. Lanctôt, Krista L., et al. "Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta‐analysis." Canadian Medical Association Journal169.6 (2003): 557‐564. 2. Rolinski, Michal, et al. "Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease." Cochrane Database Syst Rev 3 (2012). 3. Massoud, Fadi. "Cholinesterase Inhibitors in Vascular Cognitive Impairment."The Canadian Journal of Neurological Sciences 40.4 (2013): 446‐447. 4. Kavirajan, Harish, and Lon S. Schneider. "Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta‐analysis of randomised controlled trials." The Lancet Neurology 6.9 (2007): 782‐792. 5. Wild, Rebecca, T. A. C. L. Pettit, and Alistair Burns. "Cholinesterase inhibitors for dementia with Lewy bodies." Cochrane Database Syst Rev 3.3 (2003). 6. Cholinesterase inhibitors: tremor and exacerbation of Parkinson's disease. Prescrire international [1167‐7422] anonymous yr:2007 vol:16 iss:91 pg:197 ‐8 7. Mendez, Mario, Edward Lauterbach, and Shirlene Sampson. "An evidence‐based review of the psychopathology of frontotemporal dementia: a report of the ANPA Committee on Research." The Journal of neuropsychiatry and clinical neurosciences 20.2 (2008): 130‐149. 8. Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence‐based recommendations. Am J Geriatr Psychiatry. 2003 Mar‐Apr;11(2):131‐45. 9. Blackburn, D. F., et al. "Do prior authorization policies discourage first‐line antipsychotic use in patients newly discharged from a hospitalization for schizophrenia in Saskatchewan?." Journal of population therapeutics and clinical pharmacology= Journal de la therapeutique des populations et de la pharamcologie clinique 21.1 (2013): e31‐7. 10. Tariot PN. Contemporary issues in the treatment of Alzheimer’s disease: tangible benefits of current therapies. J Clin Psychiatry. 2006;67 Suppl 3:15‐22. 11. Courtney C, Farrell D, Gray R, et al. Long‐term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised doubleblind trial. Lancet. Jun 26, 2004;363(9427):2105‐2115. 12. Courtney C, Farrell D, Gray R, et al.; AD2000 Collaborative Group. Long‐term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double‐blind trial. Lancet. 2004 Jun 26;363(9427):2105‐15. 13. Gauthier, Serge, et al. "Recommendations of the 4th Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4)."Canadian Geriatrics Journal 15.4 (2012): 120. 14. Bentué‐Ferrer, Danièle, et al. "Clinically significant drug interactions with cholinesterase inhibitors." CNS drugs 17.13 (2003): 947‐963. 15. Sink, Kaycee M., et al. 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"The use of a cholinesterase inhibitor review committee in long‐term care." Journal of he American Medical Directors Association 8.4 (2007): 243‐247. Just Released, October 2014… Also look for our geriatrics book… RxFiles Drug Comparison Charts – 10th Edition Geri‐RxFiles: Assessing Medications in Older Adults DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region (SHR). Neither the authors nor Saskatoon Health Region nor any other party who has been involved in the preparation or publication of this work warrants or
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are encouraged to confirm the information contained herein with other sources. Additional information and references online at www.RxFiles.ca
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GERI‐RXFILES ANTICHOLINERGIC REFERENCES 1
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Drugs with Anticholinergic Activity. Canadian Pharmacist's Letter 2011; 27(12):271206. ADDITIONAL REFERENCES Anticholinergic Cognitive Burden Scale http://www.indydiscoverynetwork.org/AnticholinergicCognitiveBurdenScale.html Campbell NL, Boustani MA, Lane KA, et al. Use of anticholinergics and the risk of cognitive impairment in an African American population. Neurology. 2010 Jul 13;75(2):152‐9. Carrière I, Fourrier‐Reglat A, Dartigues JF, et al. Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3‐city study. Arch Intern Med. 2009 Jul 27;169(14):1317‐24. Han L, Agostini JV, Allore HG. Cumulative anticholinergic exposure is associated with poor memory and executive function in older men. J Am Geriatr Soc. 2008 Dec;56(12):2203‐10. Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects. Kennedy J, Deberdt W, Siegal A, et al. Olanzapine does not enhance cognition in non‐agitated and non‐psychotic patients with mild to moderate Alzheimer's dementia. Int J Geriatr Psychiatry. 2005 Nov;20(11):1020‐7. Lackner TE, Wyman JF, McCarthy TC, Monigold M, Davey C. Randomized, placebo‐controlled trial of the cognitive effect, safety, and tolerability of oral extended‐release oxybutynin 5mg/day in cognitively impaired nursing home residents with urge urinary incontinence. J Am Geriatr Soc. 2008 May;56(5):862‐70. n=50. 4 weeks. Short‐term treatment using oral extended‐release oxybutynin 5 mg once daily was safe and well tolerated, with no delirium, in older female nursing home participants with mild to severe dementia. Future research should investigate different dosages and long‐term treatment. Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008 Mar 10;168(5):508‐13. Sink KM, Thomas J 3rd, Xu H, Craig B, et al. Dual Use of Bladder Anticholinergics and Cholinesterase Inhibitors: Long‐Term Functional and Cognitive Outcomes. J Am Geriatr Soc. 2008 Apr 1. [Epub ahead of print] In higher‐functioning NH residents, dual use of ChIs and bladder anticholinergics may result in greater rates of functional decline than use of ChIs alone. The MDS‐
COGS may not be sensitive enough to detect differences in cognition due to dual use. Teramura‐Grönblad M, Muurinen S, Soini H, et al. Use of anticholinergic drugs and cholinesterase inhibitors and their association with psychological well‐being among frail older adults in residential care facilities. Ann Pharmacother. 2011 May;45(5):596‐602. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2012 Feb 29. Torjesen I. Anticholinergic effects of common drugs are associated with increased mortality in over 65s. BMJ. 2011 Jun 28;342:d4037. GERI‐RXFILES DEMENTIA: COGNITIVE IMPAIRMENT REFERENCES 1
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